CoChat
Sign Up
Cited by 140

The DOI matches its Crossref record; 18 of the 18 references it cites were found in a registry or an index.

Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment

Lelarge, V., Capelle, R., Oger, F., Mathieu, T., Le Calvé, B.·2024·npj Aging
DOI 10.1038/s41514-024-00138-4PMC PMC10847408
Open this paper in CoChat — free account

Abstract

The involvement of cellular senescence in the initiation and propagation of diseases is clearly characterized, making the elimination of senescent cells essential to treat age-related diseases. The development of senolytic drugs demonstrated that targeting these cells limits the deterioration of patients’ condition, by inducing apoptosis. Nevertheless, the first generations of senolytics which has been developed displayed their activities through specific mechanisms and demonstrated several limitations during clinical development. However, the rational to eliminate senescent cells remains evident, with the necessity to develop specific therapies in a context of diseases and tissues. The evolutions in the field of drug discovery open the way to a new generation of senolytic therapies, such as immunological approaches (CAR-T cells, Antibody-Drug Conjugated or vaccines), which require preliminary steps of research to identify markers specifically expressed on senescent cells, demonstrating promising specific effects. Currently, the preclinical development of these strategies appears more challenging to avoid strong side effects, but the expected results are commensurate with patients’ hopes for treatments. In this review, we highlight the fact that the classical senolytic approach based on drug repurposing display limited efficacy and probably reached its limits in term of clinical development. The recent development of more complex therapies and the extension of interest in the domain of senescence in different fields of research allow to extend the possibility to discover powerful therapies. The future of age-related diseases treatment is linked to the development of new approaches based on cell therapy or immunotherapy to offer the best treatment for patients.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41514-024-00138-4

Cites

18 of 18 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Show all 18 references

Research works printed but not linked: 56

  1. Hernandez-Segura, A., Nehme, J. & Demaria, M. Hallmarks of Cellular Senescence. Trends Cell Biol. 28, 436–453 (2018). · DOI · Paper page
  2. McHugh, D. & Gil, J. Senescence and aging: Causes, consequences, and therapeutic avenues. J. Cell Biol. 217, 65–77 (2018). · DOI · Paper page
  3. Prasanna, P. G. et al. Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy. J. Natl. Cancer Inst. 113, 1285–1298 (2021). · DOI
  4. Calcinotto, A. et al. Cellular Senescence: Aging, Cancer, and Injury. Physiol. Rev. 99, 1047–1078 (2019). · DOI · Paper page
  5. Raffaele, M. & Vinciguerra, M. The costs and benefits of senotherapeutics for human health. Lancet Healthy Longevity 3, 67–77 (2022). · DOI · Paper page
  6. Hu, L. et al. Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development. Front. Cell Develop Biol. 10, 822816 (2022). · DOI
  7. Kirkland, J. L. & Tchkonia, T. Cellular Senescence: A Translational Perspective. EBioMed. 21, 21–28 (2017). · DOI · Paper page
  8. Soto-Gamez, A., Quax, W. J. & Demaria, M. Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions. J. Mol. Biol. 431, 2629–2643 (2019). · DOI · Paper page
  9. Yang, H. et al. Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis. Aging 12, 12750–12770 (2020). · DOI
  10. Gil, T.-H. et al. Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis. Aging 14, 6006–6027 (2022). · DOI
  11. Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435 (2016). · DOI · Paper page
  12. Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMed. 36, 18–28 (2018). · DOI · Paper page
  13. Ijima, S. et al. Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis. Front. Immunol. 13, 960601 (2022). · DOI
  14. Liu, L. et al. Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle. Aging 14, 7650–7661 (2022). · DOI
  15. Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science (1979) 373, eabe4832 (2021).
  16. Marinova, M., Solopov, P., Dimitropoulou, C., Colunga Biancatelli, R. M. L. & Catravas, J. D. Acute exposure of mice to hydrochloric acid leads to the development of chronic lung injury and pulmonary fibrosis. Inhal. Toxicol. 31, 147–160 (2019). · DOI
  17. Sibinska, Z. et al. Amplified canonical transforming growth factor-β signalling via heat shock protein 90 in pulmonary fibrosis. Eur. Resp. J. 49, 1501941 (2017). · DOI
  18. Sontake, V. et al. Hsp90 regulation of fibroblast activation in pulmonary fibrosis. JCI Insight 2, e91454 (2017). · DOI
  19. Chen, D. D. et al. HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells. Aging 13, 21547–21570 (2021). · DOI · Paper page
  20. Han, X. et al. FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway. J. Cell Mol. Med. https://doi.org/10.1111/jcmm.17333. (2022). · DOI
  21. Chin, A. F. et al. Senolytic treatment reduces oxidative protein stress in an aging male murine model of post-traumatic osteoarthritis. Aging Cell https://doi.org/10.1111/acel.13979. (2023). · DOI
  22. Hsu, B. et al. Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101. Osteoarthritis Cartilage 28, S479–S480 (2020). · DOI
  23. He, Y. et al. Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity. Aging Cell 19, e13117 (2020). · DOI
  24. Zhao, X.-B. et al. P22077 inhibits LPS-induced inflammatory response by promoting K48-linked ubiquitination and degradation of TRAF6. Aging 12, 10969–10982 (2020). · DOI
  25. Lin, Y. C. et al. USP7 promotes the osteoclast differentiation of CD14+ human peripheral blood monocytes in osteoporosis via HMGB1 deubiquitination. J. Orthop. Translat. 40, 80–91 (2023). · DOI
  26. Guerrero, A. et al. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell 19, e13133 (2020). · DOI · Paper page
  27. Wang, K. et al. KDM4C-mediated senescence defense is a targetable vulnerability in gastric cancer harboring TP53 mutations. Clin Epigenetics 15, 163 (2023). · DOI
  28. Meiners, F., Secci, R., Sueto, S., Fuellen, G. & Barrantes, I. Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data. https://doi.org/10.1101/2022.05.26.492763 (2022). · DOI
  29. Pramotton, F. M. et al. DYRK1B inhibition exerts senolytic effects on endothelial cells and rescues endothelial dysfunctions. Mech. Ageing Dev. 213, 111836 (2023). · DOI
  30. Lee, K-A., Flores, RR., Jang, IH., Saathoff, A. & Robbins, PD. Immune Senescence, Immunosenescence and Aging. Front. Aging. 3, 900028 (2022). · DOI · Paper page
  31. Giannoula, Y., Kroemer, G. & Pietrocola, F. Cellular senescence and the host immune system in aging and age-related disorders. Biomed. J. 46, 100581 (2023). · DOI
  32. Kurioka, A. & Klenerman, P. Aging unconventionally: γδ T cells, iNKT cells, and MAIT cells in aging. Seminars Immunol. 69, 101816 (2023). · DOI
  33. Naigeon, M. et al. Human virome profiling identified CMV as the major viral driver of a high accumulation of senescent CD8 + T cells in patients with advanced NSCLC. Sci. Adv. 9, eadh0708 (2023). · DOI
  34. Wang, T. W. et al. Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes. Nature 611, 358–364 (2022). · DOI · Paper page
  35. Shapiro, M. R. et al. Human immune phenotyping reveals accelerated aging in type 1 diabetes. JCI Insight 8, e170767 (2023). · DOI
  36. Schloesser, D. et al. Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis. J. Cell Biol. 222, e202207097 (2023). · DOI
  37. Jatal, R. et al. Sphingomyelin nanosystems decorated with TSP-1 derived peptide targeting senescent cells. Int. J. Pharm. 617, 121618 (2022). · DOI
  38. Poblocka, M. et al. Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker. Sci. Rep. 11, 20358 (2021). · DOI · Paper page
  39. Takaya, K., Asou, T. & Kishi, K. New Senolysis approach via antibody-drug conjugate targeting of the senescent cell marker Apolipoprotein D for Skin Rejuvenation. Int. J. Mol. Sci. 24, 5857 (2023). · DOI
  40. Amor, C. et al. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat. Aging https://doi.org/10.1038/s43587-023-00560-5 (2024). · DOI · Paper page
  41. Yang, D. et al. NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Sci. Transl. Med. 15, eadd1951 (2023). · DOI · Paper page
  42. Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 20, 359–371 (2023). · DOI
  43. Gajra, A. et al. Barriers to Chimeric Antigen Receptor T-Cell (CAR-T) Therapies in Clinical Practice. Pharmaceut. Med. 36, 163–171 (2022).
  44. Noll, J. H., Levine, B. L., June, C. H. & Fraietta, J. A. Beyond youth: Understanding CAR T cell fitness in the context of immunological aging. Semin. Immunol. 70, 101840 (2023). · DOI
  45. Zheng, Z. et al. Fine-Tuning through Generations: Advances in Structure and Production of CAR-T Therapy. Cancers 15, 3476 (2023). · DOI
  46. Lear, T. B. & Finkel, T. Senolytic vaccination: a new mandate for cardiovascular health? J. Cardiovasc. Aging 2, 17 (2022).
  47. Jiang, S. S. et al. Gene expression profiling suggests a pathological role of human bone marrow-derived mesenchymal stem cells in aging-related skeletal diseases. Aging 3, 672–684 (2011). · DOI
  48. Mendelsohn, A. R. & Larrick, J. W. Antiaging Vaccines Targeting Senescent Cells. Rejuvenation Res. 25, 39–45 (2022). · DOI
  49. Chung, J.-S., Bonkobara, M., Tomihari, M., Cruz, P. D. & Ariizumi, K. The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses. Eur. J. Immunol. 39, 965–974 (2009). · DOI
  50. Tomihari, M., Chung, J.-S., Akiyoshi, H., Cruz, P. D. & Ariizumi, K. DC-HIL/glycoprotein Nmb promotes growth of melanoma in mice by inhibiting the activation of tumor-reactive T cells. Cancer Res. 70, 5778–5787 (2010). · DOI
  51. Després, J.-P. Is visceral obesity the cause of the metabolic syndrome? Ann. Med. 38, 52–63 (2006). · DOI
  52. Yoshida, S. et al. The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nat. Commun. 11, 2482 (2020). · DOI · Paper page
  53. Wang, B., Kohli, J. & Demaria, M. Senescent Cells in Cancer Therapy: Friends or Foes?. Trends Cancer 6, 838–857 (2020). · DOI · Paper page
  54. Liu, Y. et al. Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells. J. Immunother. Cancer 11, e005862 (2023). · DOI
  55. Hong, J. et al. Senescent cancer cell-derived nanovesicle as a personalized therapeutic cancer vaccine. Exp. Mol. Med. 55, 541–554 (2023). · DOI
  56. Marin, I. et al. Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity. Cancer Discov. 13, 410–431 (2023). · DOI

Cited by

Sorted by citations

See all 140

Metadata

Authors
Lelarge, V., Capelle, R., Oger, F., Mathieu, T., & Le Calvé, B.
Venue
npj Aging
Publisher
Springer Science and Business Media LLC
Published
2024-02-06
Volume
10
Issue
1
ISSN
2731-6068
DOI
10.1038/s41514-024-00138-4
PMC
PMC10847408
Cited by
140
References
18
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review